Amino alkoxy phenyl methanes



United States Patent Ofiice 2,891,957 Patented June 23, 1959 AMINOALKOXY PHENY L ME'IHANES Robert E. Allen, Wyoming, and Frank P.Palopoli, Cincinnati, Ohio, Edward L. Schumann, Kalamazoo, and WilliamC. Day, Lansing, Mich., and Vernon J. Feil, Cincinnati, Ohio, assignorsto The Wm. S. Merrell Company No Drawing. Application February 21, 1958Serial No. 716,565

6 Claims. (Cl. 260-2945) Our invention relates to new chemical compoundswhich can be regarded as amino ethers of benzaland benzylcarboheterocycles. They are distinguished, in general, by theiranti-estrogenic activity in the endocrine system, anti-inflammatoryactivity, anti-gonadotrophic activity, activity in decreasing bloodcholesterol levels, activity in thyroid conditions, activity in therespiratory system and anti-fungal activity. Some of the compoundspossess various combinations of these properties.

As estrogen antagonists, the compounds are useful in the treatment ofhyperestrogenism and disorders related to this condition, e.g., ovarianhyperfunction, endometriosis, Kleinfelters syndrome, dysmenorrhea,amenorrhea, menopausal dysfunction, functional bleeding, sexualprecocity and similar conditions. They are active both orally andparenterally and so can be administered by either route, though the oralroute is preferred in most instances. Some of the compounds have a highdegree of activity as estrogen antagonists and are also advantageouslynonestrogenic. Some of the compounds with anti-estrogenic activity arealso uterotrophic.

As anti-inflammatory agents, the compounds are useful in alleviating thesymptoms of such collagen diseases as arthritis and rheumatism and inthe topical treatment of inflammation. Some of the compounds possess thenovel combination of anti-inflammatory and anti-estrogenic activitiesand are especially advantageous for this reason. They are usefultopically, orally and parenterally for this purpose.

As blood cholesterol level depressants, the compounds are useful in thetreatment of cardiovascular diseases such as atherosclerosis. They areuseful orally for this purpose.

As gonadotrophic inhibition agents, the compounds are useful for thetreatment of fertility and sterility problems and can be administeredorally or parenterally for this purpose.

The compounds are also useful in treating respiratory diseases and areuseful orally or intranasally for this purpose. Some of the respiratoryinfections that can be treated are common cold, influenza, sinusitis,whooping cough, adenovirus, and pneumonia of different etiologies.

The compounds are also useful in treating thyroid conditions as theyexhibit activity in reducing thyroid weight. They are useful orally andparenterally for this purpose.

As anti-fungal agents, the compounds are useful in the topical treatmentof fungus infections such as torulosis, ring worm, athletes foot,blastomycosis, histoplasmosis,

from 0.1 mg. to 5 grams daily, depending on the compound and conditionunder treatment. Parenterally, they can be used in doses ranging between0.1 mg. and 1 gram daily depending on the compound and condition undertreatment. Some irritation may be encountered. For topical use thecompounds can be incorporated into creams, ointments or lotions inconcentrations of up to 10 percent. Intranasally, e.g., in nose dropsand atomizers, the concentration can be in the order of about 0.1 to 2percent.

The compounds can be used as the free base. Some of the compounds can beisolated and used in the form of their salts with inorganic acids, e.g.,hydrochloric or hydrobromic acids, or organic acids such as. citricacid, oxalic acid and the like. The compounds can also be isolated andused in the form of their N-oxides and their quaternary salts withquaternizing agents such as lower alkyl sulfates, e.g., methyl sulfates.Such salts are useful for special purposes.

The novel compounds of our invention are amino ethers of benzalandbenzyl-carboheterocycles. They can be represented by the followingformulas:

(a) The benzal compounds:

0 o .HMA (b) the benzyl compounds:

I l 0 C nHfl A and (c) the benzyl compounds:

(|)H O CnHzn The AC H O group is attached to the benzene ring in themeta or para position. A is amino, or alkylami'no in which the alkylgroup contains from 1 to 4 carbon atoms, or dialkylamino in which thealkyl group contains from 1 to 4 carbon atoms, dibenzylamino, or an N-heterocycle such as morpholino, piperidino, or N-methylpiperazino and nis 2 or 3. Y is hydrogen or methyl. R is a fluorenylidene, indenylidene,tetrahydronaphthylidene, Xanthylidene or thioxanthylidene radical. R isa tinea capitis, and monila infections. They are also usefiuorenyl,indenyl, tetrahydronaphthyl, xanthyl, thioxanthyl or anthryl radical.

Expressed in another Way R and R are wherein B represents a bond in R(the benzal compounds), B is hydrogen in R (the benzyl compounds), and Zis oxygen or sulfur in R and oxygen, sulfur or methylene (CH in R.

In the benzyl compounds of Formulas b and c, the compounds in which R isfluorenyl are particularly preferred.

The novel benzal compounds can be prepared by four general methods,i.e.,

(1) By the reaction of a hydroxy-benzal compound, substituted with an Rgroup, with a dihaloalkane, e.g., a bromochloro-alkane or a dibromoordichloro-alkane, followed by reaction with a suitable amine, i.e.,

n=cn (Han man (2) By the reaction of the hydroxy-benzal compound of (1)with a haloalkylamino compound, e.g., a dialkylaminoalkyl halide or ahaloalkylheterocyclic, i.e.,

O CnHg A (3) By the reaction of a benzaldehyde substituted with a AC H Ogroup with the compound from which R is derived, e.g., fiuorene, in thepresence of an alkaline catalyst, e.g., sodium methoxide or ethoxide,i.e.,

-CHO RH;

OGDH A AC H O o omiiQ RHLl (from an, BuLi) In the above methods R hasthe same meaning as in the novel benzal compounds of Formula a describedabove except that, in method 2, R is not indenylidene, and in method 4 Rcan be anthrylene. Also, the phenolic starting materials of methods 1and 2 are preferably used in the form of their alkali metal salts, e.g.,sodium, lithium or potassium.

The novel benzyl compounds of Formula c can be generally prepared bymethod 4.

The novel benzyl compounds of Formula 22 can be prepared by thehydrogenation, preferably in the presence of a catalyst, e.g., platinumor palladium on charcoal, of the corresponding benzal compounds, i.e.,

1" Y Q 5Q OC H A H oc,,H ,A The benzyl compounds (b) in which R isanthryl can be prepared by method 2 using a hydroxy-benzyl-anthracenestarting material which can be prepared by method (c) below fromanthrone. In method below when anthrone is used ahydroxy-benzyl-anthracene is obtained rather than ahydroxy-benzal-dihydroanthracene.

The novel benzyl compounds of Formula b or c in which A is amino canalso be prepared by the hydrogenolysis of the corresponding benzalcompound wherein A is dibenzyl amino.

The hydroxy-benzal intermediates used to prepare the new benzalcompounds can be prepared by four general methods, i.e.z

(a) Reacting a compound from which R is derived, eg, fiuorene, withmethoxy-benzaldehyde in the presence of a condensing agent such assodium methoxide or ethoxide or piperidine to form the correspondingmethoxy-benzal compound, and demethylating, e.g., with pyridine-HCl,hydrobromic acid or aluminum chloride, to produce the hydroxy-benzalcompound, i.e.,

NaOMe RH; CHO

Me O

OMe OH (12) Reacting the R starting compound of (a) withm-hydroxybenzaldehyde, i.e.,

HO OH (0) Reacting a ketone containing R with a methoxybenzyl magnesiumhalide to form the corresponding methoxybenzal compound anddemethylating as in meth- 0d (a), i.e.,

and

(d) Reacting the R starting compounds of (a) with the tetrahydropyranylether of hydroxybenzaldehyde, i.e.,

As noted above, an exception to method (0) is the behavior of anthrone(R anthrylene) which forms benzylmethoxy and benzyl-hydroxyintermediates rather than benzal intermediates, i.e.,

OMe

This benzyl intermediate can be used in method 2 above to produce thenovel benzyl compounds wherein R is anthryl.

The novel compounds of our invention will be further illustrated by thefollowing examples.

EXAMPLE 1 9- [p-( fi-ethylaminoethoxy) benzal] fluorene demethylate andA mixture of 735 g. of 9-anisalfluorene and 1070 g. of pyridinehydrochloride was refluxed for 30 minutes, cooled, and the mixture wasshaken in water and ether. The ether solution was extracted twice with10 percent sodium hydroxide solution, this alkaline solution was at roomtemperature for prolonged periods, crystals of9-(phydroxybenzal)fluorene were obtained, melting at 110-112" C. Thisphenol was sufficiently pure for subsequent reactions to form otherswithout the need for crystallization. The residue obtained byacidification of the above alkaline solution was either taken up in aknown volume of ethanol or dry benzene and aliquot portions used.

A mixture of 82 g. of 9-(p-hydroxybenzal)fluorene and 18 g. of sodiummethoxide in 300 ml. of ethanol was stirred for 30 minutes, 180 g. ofl-bromo-Z-chloroethane was added and the mixture was refluxed 8 hours.The ethanol and bromoohloroethane were removed and a chloroform solutionof the residue was washed with percent sodium hydroxide, water, thendried over anhydrous magnesium sulfate. The chloroform was removed andthe oily residue, when taken up in ether, settled out as crystals of9-[p-(B-chloroethoxy)benzal]fluorene, melting at 122-123" C.

A mixture of 89 g. of 9-[p-(fi-chloroethoxyybenzal]- fluorene and 60 g.of ethylamine in 240 ml. of ethanol was heated in a pressure bottle for24 hours at 72 C. The excess ethylamine and ethanol were removed and theresidue was acidified in ethanol with alcoholic hydrogen chloride. Afterremoving the ethanol and washing the solid with anhydrous ether, theproduct was triturated three times with hot chloroform, thencrystallized from ethanol to give 9- [p-(fi-ethylaminoethoxyfibenzel]fluorene hydrochloride, melting at 235-236C.

Analysis.-Calcd. for C H NO-HCh C, 76.30; H, 6.40; CI, 9.38. Found: C,76.01; H, 6.46; Cl, 9.25.

This compound exhibits the following activities: antiinflammatory;uterotrophic; produces mouse lung consolidation arrest; antifungal.

EXAMPLE 2 9- [p- (B-dimethylaminoethoxy) benzal] fluorene A mixture of30 g. of 9-(p-hydroxybenzaDfluorene and 6.5 g. of sodium methoxide in150 ml. of ethanol was stirred 30 minutes then was allowed to refluxwith a solution of ,B-dimethylaminoethyl chloride (prepared from 21 g.of the hydrochloride salt) in 150 ml. of toluene for four hours. Thesolvent was removed,'the residue was taken up in ether and after washingtwice with 10 percent sodium hydroxide solution and three times withwater the ethereal solution was dried over anhydrous magnesium sulfate.After rendering this solution slightly acidic with alcoholic hydrogenchloride and removing the ether, the product was crystallized frommethanolisopropanol to give 9-[p-(fi-dimethylaminoethoxy)benzal]fiuorenehydrochloride, melting at 217 C.

Analysis.-Calcd. for C H NO-HCl: C, 76.28; H, 6.40; N, 3.71. Found: C,75.90; H, 6.41; N, 3.82.

, This compound exhibits the following activities: antiinflammatorry;antifungal.

EXAMPLE 3 When the fi-dimethylaminoethyl chloride was replaced with,B-diethylaminoethyl chloride in the procedure of Example 2, thehydrochloride salt of 9-[p-(fi-diethylaminoethoxy)benzal1fluorene wasobtained (from chloroform-ethyl acetate), melting at 196197 C.

Analysis.Calcd. for C H NO-HCl: C, 76.93; H, 6.95; N, 3.45. Found: C,76.71; H, 7.29; N, 3.38.

This compound can also be prepared by the following procedure:

To 175 ml. of refluxing dihydropyran, containing four drops ofconcentrated hydrochloric acid, was added 36.6 g. of'p-hydrox'ybenzaldehyde. After refluxing an hour,

the excess dihydropyran was removed by distillation at 25 mm. ofpressure. One-half of the residue was dissolved in ml. of ethanol andadded to a mixture of 16.6 g. of fluorene and 16.6- g. of sodiummethoxide in 200ml. of ethanol. The mixture was refluxed an hour,

the solvent was removed and the residue taken up in ether. After washingthe ether solution with water, then with saturated aqueous solution ofsodium bisulfite, and again with water, 100 ml. of 10 percenthydrochloric acid was added and the ether was allowed to evaporate byheating on a steam bath. An ether extract of the organic layer wasextracted with 10 percent sodium hydroxide, the aqueous layer wasacidified with 10 percent hydrochloric acid and the precipitated oil wasdissolved in ether, washed with water, dried over magnesium sulfate, andthe solvent was removed. The residue was 9(p-hydroxybenzal)fluorenewhich, when allowed to react (as the sodium salt) withB-diethylaminoethyl chloride, gave9-[p-(B-diethylaminoethoxy)benzal]-fluorene, whose hydrochloride saltwas identical with the above.

This compound exhibits the following activities: antiinflammatory;produces mouse lung consolidation arrest; antifungal.

EXAMPLE 4 9- [m- (p-diezhylam inoethoxy) benzal] fluorene A mixture of41.5 g. of fluorene and 54 g. of sodium methoxide in 450 ml. of ethanolwas warmed to 65 C. and 30.6 g. of m-hydroxybenzaldehyde in 300 ml. ofethanol was added with stirring. After standing at room temperature for16 hours and then refluxing for 6 hours, the mixture was diluted with anexcess of 10 percent hydrochloric acid and extracted with benzene. Theorganic layer was extracted with 10 percent sodium hydroxide solution,the aqueous layer was acidified and extracted with benzene and thebenzene solution was dried over anhydrous magnesium sulfate. Thesolution was distilled to give 9-(m-hyd'roxybenzal)-fluorene, boiling at232 at 0.2 mm.

Following the procedure of Example 3, the 9-(mhydroxybenzaDfluorene (asthe sodium salt) was treated with ediethylarninoethyl chloride to give9-[m-(B-diethylaminoethoxy)benzal]fluorene Whose hydrochloride saltmelted at 193-195 C. (from isopropanol).

Analysis.-Calcd. for c, H, N0-Hc1: C, 76.93; H, 6.95; N, 3.45. Found: C,76.70; H, 7.17; N, 3.44.

This compound exhibits the following activities: antiinflammatory;decreases thyroid weight; antifungal; phospholipogenic.

EXAMPLE 5 9- [p- ('y-dim'ethylaminopropoocy) benzaflflu'orene EXAMPLE 69- [p- 'y-diethylwmtin0pr0p0oty) benzal] fluore ne A mixture of 20 g. of9-(p-hydroxybenzal)fluorene and 4 g. of sodium methoxide in ml. of drybenzene was refluxed two hours, a solution of y-diethylarninopropylchloride (prepared from 22.3 g. of its hydrochloride salt) in 150ml. oftoluene was added and the mixture was stirred and refluxed 16 hours.Following the Work-up de scribed in Example 2, the hydrochloride salt of9[p'-('y diethylarninopropoxy) benzalJfiuorene was obtained (fromisopropanol), melting ati203'-204 C.

7 Analysis.-Calcd. for CgqHggNOHClI C, 77.22; H, 7.20; N, 3.34. Found:C, 76.84; H, 7.13; N, 3.55.

This compound exhibits the following activities: antiinflammatory;antifungal.

EXAMPLE 7 9- [p-(y-dibutylaminoethoxy) benzal] fiuorene Whenfi-di-n-butylaminoethyl chloride replaced the dimethylaminoethylchloride in the procedure of Example 2, the hydrochloride salt of9-[p-(B-dibutylaminoethoxy)- benzallfluorene was obtained (fromisopropanol), melting at 170171 C.

Analysis.Calcd. for C H NO-HCl: C, 78.00; H, 7.86; N, 3.03. Found: C,77.88; H, 8.07; N, 2.97.

This compound exhibits the following activities: antiinflammatory;produces mouse lung consolidation arrest.

EXAMPLE 8 9- p- ,B-a' i b enzy laminoeth oxy benzal fiuorene A mixtureof 33 g. of 9-[p-(fi-chloroethoxy)benzal]- fiuorene and 40 g. ofdibenzylamine was heated at 160- 190 C. for 34 hours, the mixture wastriturated several times with benzene and the benzene was removed. Theresidual oil was triturated with 40-60 petroleum ether three times, theresidue was acidified with alcoholic hydrogen chloride and aftercrystallizing twice from ethanol, the hydrochloride salt of9-[p-(fi-dibenzylaminoethoxy)- benzallfluorene was obtained, melting at180-182" C.

Analysis.-Calcd. for C H NO-HCl: C, 81.56; H, 6.09; N, 2.64. Found: C,81.92; H, 5.93; N, 2.64.

This compound exhibits the following activities: uterotrophic.

EXAMPLE 9 Alpha- [p-(fl-diethylaminoethoxy)phenyl] -alpha- (9-flu0renyl)ethanol A solution of butyl lithium (from 2.5 g. of lithium wire and24.7 g. butyl bromide in 150 ml. dry ether) was added to a solution of25 g. of fiuorene in 150 ml. of dry ether and after stirring 30 minutes,a solution of 35.2 g. of p-(B-diethylaminoethoxy)-acetophenone in 100ml. of dry ether was added slowly with stirring. The mixture wasdecomposed with cold water, the ethereal solution was washed repeatedlywith water, was dried over anhydrous magnesium sulfate and the solventwas replaced with isopropanol. Crystals ofalpha[p-(Bdiethylarninoethoxy)phenyl] alpha (9 fiuorenyl)ethanol wereobtained, melting at 104 C.

Analysis.-Calcd. for 14 810 C, 80.76; H, 7.78; N, 3.49. Found: C, 80.86;H, 7.85; N, 3.47.

This compound exhibits the following activities: antiinfiammatory;estrogen antagonist; cholesterol depressant and phospholipogenic;antifungal.

Alpha [p (,8 diethylaminopropoxy)phenyl] alpha- (l-indenyl)methanol wasprepared by the procedure of Example 9 utilizing indene and 4 (adiethylaminopropoxy)benzaldehyde (prepared from p-hydroxybenzaldehydeand a-diethylaminopropyl chloride), which had a boiling point of 142l44C. (0.5 mm.) The product formed a dihydrogen citrate monohydrate meltingat 94 C. with decomposition.

Analysis.-Calcd. for C H NO -C I-I O -H O: C, 62.00; H, 7.00; N, 2.50.Found: C, 61.76; H, 6.86; N, 3.02.

EXAMPLE l0 9-[alpha-methyl-p- (fi-diethylaminoethoxy) benzal] fiuoreneThe ethanol of Example 9 was dehydrated by refluxing in alcoholcontaining an excess of hydrogen chloride for six hours. Upon cooling, acrystalline product settled out which was recrystallized from ethanol,then dried at 160 C. at 0.5 mm. to give the hydrochloride salt of 9-[alpha methyl p (B diethylaminoethoxy)benzal]- fluorene, melting at22l223 C.

8 Analysis.Calcd. for C H NO-HCl: C, 77.20; H, 7.20; N, 3.34. Found: C,77.18; H, 7.44; N, 3.36.

This compound exhibits the following activities: antiinflammatory;uterotrophic.

EXAMPLE 1 1 9- p- B-piperidinoethoxy) benzal] fiuorene When thefl-dirnethylaminoethyl chloride was replaced withN-fl-chloroethylpiperidine in the procedure of Example 2, thehydrochloride salt of 9-[p-(B-piperidinoethoxy)'oenzallfluorene wasobtained (for methanolchloroform) which, after drying at 150 C. at 0.5mm., melted at 2l52l6 C.

Analysis.-Calcd. for CzqHzqNO'HCll C, 77.57; H, 6.75; N, 3.35. Found: C,77.99; H, 6.27; N, 3.09.

This compound exhibits the following activities: uterotrophic;gonadotrophic inhibitor; produces mouse lung consolidation arrest;antifungal.

EXAMPLE 12 9- p- ,B-morpholinoethoxy) benzal] fiuorene When thefi-dimethylaminoethyl chloride was replaced withN-[i-chloroethylmorpholine in the procedure of Example 2, thehydrochloride salt of 9-[p-(fi-morpholinoethoxy)benzallfluorene wasobtained (from ethanol), melting at 208-2l0 C.

Analysis.-Calcd. for CZGHZ5NOZ'HCIZ C, 74.36; 6.24; N, 3.34. Found: C,74.24; H, 6.31; N, 3.57.

This compound exhibits the following activities: antiinflammatory(dextran edema test).

EXAMPLE l3 9- p- B-4-methylpiperazinoethoxy benzal1fluorene A mixture of50 g. of p-hydroxybenzaldehyde and 22.4 g. of sodium methoxide in 150m1. of methanol and 300 ml. of xylene was heated until all the methanolhad been removed. A solution of [3-4-methylpiperazinoethyl chloride(prepared from 122 g. of the dihydrochloride salt, 69 g. KOH andapproximately 75 ml. water) in xylene was added while the sodium saltwas being stirred and refluxed. After 16 hours of refluxing, the xylenesolution was washed with 10 percent sodium hydroxide, then water anddistilled to give 4-(,B-4-methylpiperazinoethoxy)benzaldehyde, boilingat 168 C. at 0.2 mm.

A mixture of 12.7 g. of fiuorene and 12.9 g. of sodium methoxide in ml.of ethanol was heated with stirring for 30 minutes. A solution of 19 g.of the above benzaldehyde in 100 ml. of ethanol was added and themixture stood overnight at room temperature. After refluxing an hour,the ethanol was removed, the residue was dissolved in ether and washedwith water. The ether solution was then extracted with 10 percenthydrochloric acid, the aqueous layer was rendered basic with 10 percentsodium hydroxide and the oily precipitate was taken up in ether, driedover anhydrous magnesium sulfate and acidified with alcoholic hydrogenchloride. The yellow solid was boiled in ethanol and filtered while hotfrom the insoluble portion. The filtrate was cooled and the yellowcrystals obtained were dried in vacuo at 100. The dihydrochloride of9-[p-(B-4-methylpiperazinoethoxy)benzal]fluorene melted at 261-264 C.

Analysis.Calcd. for C H N O-2HCl: C, 69.08; H, 6.44; N, 5.97. Found: C,69.13; H, 6.81; N, 5.70.

EXAMPLE 14 9-[p-( -piperidinopropoxy) benzallfluorene When-piperidinopropyl chloride replaced the fi-dimethylaminoethyl chloridein the procedure of Example 2, the hydrochloride salt of 9-p-('-piperidinopropoxy)- benzal fiuorene was obtained, melting at 246248 C.

Analysis.Calcd. for C H NO-HCl: C, 77.84; H, 7.00; N, 3.24. Found: C,78.04; H, 7.30; N, 3.21.

This compound exhibits the following activities: antiinflammatory;antifungal.

A mixture of 13 g. of indcne and 6.1 t. of sodium methoxide in 100 ml.of ethanol was refluxed an hour then a solution of 22 g. of4-(p-diethylaminoethoxy)- benzaldehyde in 100 ml. ethanol was added andrefluxing was continued for two hours. The alcohol was removed, theresidue was taken up in either, extracted with percent hydrochloricacid, the aqueous layer was rendered basic and extracted with ether. Thedried ether solution was acidified with'alcoholic hydrogen chloride andthe precipitated oil was crystallized from methylene chloride-benzene togive the hydrochloride salt of l-[p-(fi-diethylaminoethoxy)benzallindene, melting at 197- 198 C.

AnalysinfiCalcd. for C H NO-HCl: C, 74.25; H, 7.36; N, 3.94. Found: C,73.89; H, 7.22; N, 4.07.

This compound exhibits the following activities: antiinflammatory;gonadotrophic inhibitor or androgen antagonist; decreases thyroidweight; increases adrenal weight; cholesterol depressant.

EXAMPLE 16 1 [pp-d 'ethylaminoethoxy ),be nzal1 tetrahydroriaphthaler eThe Grignard reagent from 102 g. of p-methoxybenzyl chloride in 1400 ml.of ether was added to a solution of 100 g. of alpha-tetralone in 300 m1.of ether and refluxed three hours. After decomposing the' mixture withdilute hydrochloric acid, the ether solution was evaporated and theresidue was refluxed in alcoholic hydrogen chloride three hours.Crystals of l-anisaltetrahydronaphthalene separated upon cooling,melting at 86-88 C.

Analysia-Calcd. for C Hi O: C, 86.38; H, 7.25. Found: C, 86.09; H, 7.32.

A mixture of 90 g. of the anisaltetrahydronaphthalene and 168 g. ofpyridine hydrochloride was heated at 200 C. for 6 hours. The mixture wastaken up in water and ether, the ether layer was extracted with 10percent sodium hydroxide, the acidified alkaline solution was extractedwith ether and the ether was replaced with ethanol-water. Crystals of1-(p-hydroxybenzal)tetrahydronaphthalene were obtained, melting at133-135 C.

An'alysis.-Calcd. for C H O: C, 86.40; H, 6.82. Found: C, 86.34; H,6.89.

When the 9-(p -hydroxybenzal)fluorene was replaced with1-(p-hydroxybenzal)tetrahydronaphthalene in the procedure of Example 3,1-[p-(,B-diethylaminoethoxy)- benzalltetrahydronaphthalene was obtainedas the hydrochloride (from ethanol), melting at 219-221 C.

Analysis.-Calcd. for C H No'HCl: C, 74.28; H, 8.13; N, 3.77. Found: C,74.42;.H, 8.25; N, 3.76.

This compound exhibits thefollowing activities: estro gen antagonist.

EXAMPLE 17 9- [p- (fl-diethylaminoethoxy) benzal] xanihene When thealpha-tetralone was replaced with xanthone in the procedure of Example16, the following intermediates and final product were obtained:

9 (p ni'ethoxybenzahxanthene (from ethanol ethyl acetate), meltingat104107 C.

9 (p hydroxybenzal)xanthene (from ethanol ethylacetate), melting at18:1-182 C.

The hydrochloride salt of 9 [p (B diethylamin'oethoxy)-benzal]xanthene(from methanol-isopropanol), melting-at 196-197 C.

Analysis.--Calcd.' for C H NO -I-ICl: C, 74.00; H, 6.69; N, 3.32; Found:C, 73.45; H, 6.78; N, 3.55.

This compound exhibits the following activities: antiinflammatory.

EXAMPLE 18 9- [p- (p-diethylwminoeth oxy) benzal] thioxanthene Wlltllli116 iillill-ltlaione Was replaced with thioxanthone in the procedin'eof Example 16, the following intermediates and final product wereobtained:

9-(p-methoxybenzal)thioxanthene (from ethyl acetatemethanol), melting at134-136 C.

9-(p-hydroxybenzal)thioxanthene (from ether-petroleum ether), melting at176-177 'C. 1

The hydrochloride salt of 9-[p-(fl-diethyl 'oethoxy)benzal] thioxanthene(from methanol-isopropanol), melting at 205 C.

Analysis.Calcd. for C H NOS'HCl: C, 71.28; H, 3.4;; N, 3.20. Found: C.71.06; H, 6.62; N, 3.15; S, 7.32,

This compound exhibits thefollowing activities: antiinflammatory: lowerscholesterol/phospholipid ratio; uterotrophic estrogen antagonist.

EXAMPLE 19 9- [p-(/E-diethylaminoethoxy)benzyllanthracene EXAMPLE 20 e9- [p- (fi-aminoethoxy benzyl] fluorene A mixture of the free basederived from 22 g. of the hydrochloride of 9- [p-(fl-dibenzylaminoethoxy) betnzal fluoren'e (Example 8) and 2 g. of 10percent palladium on charcoal in 200 ml. of ethanol was hydrogenatedunder 3 atmospheres of hydrogen until the theoretical three molarequivalents of hydrogen had been consumed. After removing the catalystand acidifying the ethanol solution with hydrogen chloride, the productobtained was recrystallized from chloroform-isopropanol to give thehydrochloride salt of 9- [p-(p-aminoethoxy)benzyUflnorene, melting at199 C. (after drying at at 0.5 mm).

A'nalysz's.Calcd. tfor c ,H,,No-Ho1; C, 75.12; H, 6.31,; N, 3.98; Found:C, 75.02; H, 6.61; N, 3.95.

This compound exhibits the following activities: orally activeanti-inflammatory; estrogen antagonist; gonadotrophic inhibitor orandrogen antagonist; decreases thyroid weight; phospholipogenic.

EXAMPLE 21 9- [pfl-ethylaminoethoxy benzyl] fluorene vA mixture of 24 g.of the hydrochloride, salt of the compound of Example 1 and 3 g. of 10percent palladium on charcoal in 250 ml. of ethanol was hydrogenatedunder 3 atmospheres of hydrogen'until the uptake of hydrogen ceased.More ethanol was added and the mixture was warmed on a steam bath todissolve the precipitated amine salt in order to remove the catalyst.After concentrating and cooling the ethanol solution, the hydrochloridesalt of 9-[p-(,B-ethylaminoethoxy)benzyl]fluorene was obtained, meltingat 217-219 C.

Analysis.-Ca=lcd. for C H NO-HCl: C, 75.90; H, 6.90; N, 3.69. Found: C,75.64; H, 6.80; N, 3.84.

This compound exhibits the following activities: antiinflammatory;uterotrophic; gonadotrophic inhibitor; cho-v lesterol depressant.

EXAMPLE 22 9- [p-( fl-dimethylaminoeth oxy) benzyl] fluorene When thehydrochloride of 9-[p-(fi-dimethylarninoethoxy)benzal]fluorene replacedthe substituted fluorene in the procedure of Example 21, thehydrochloride salt of 9 [p-(B-dimethylaminoethoxy)-benzyl]fluorene wasobtained, melting at 209211 C.

Analysis.Ca.lcd. for C H NO-HCl: C, 75.90; H, 6.90; N, 3.69. Found: 0,75.48; H, 6.95; N, 4.03.

This compound exhibits the following activities: antiinfiammatory;uterotrophic; gonadotrophic inhibitor or androgen antagonist;phospholipogenic.

EXAMPLE 23 9- [p-( fl-diethylaminoethoxy) benzyll fluorene When thehydrochloride of 9 [p-(fi-diethylaminoethoxy)benzallfluorene replacedthe substituted fluorene in the procedure of Example 21, thehydrochloride salt of 9-[p-(fi-diethylaminoethoxy)benzyl]fluorene wasobtained (from isopropanol), melting at 176-178" C. (after drying at 125C. at 0.5 mm.).

Analysis-Called. for C H NO-HCl: C, 76.52; H, 7.41; N, 3.43. Found: C,76.41; H, 7.60; N, 3.54.

This compound exhibits the following activities: antiinfiammatory;uterotrophic; antifungal.

EXAMPLE 24 9- [p-( l8-dibutylaminoethoxy) benzyl] fluorene When thehydrochloride of 9-[p-(fi-dibutylaminoethoxy)benzal]fluorene replacedthe substituted fluorene in the procedure of Example 21, thehydrochloride salt of 9-[p-(l3-dibutylaminoethoxy)-benzyl]fiuorene wasobtained (from isopropanol), melting at 156 C.

Analysis.-Calcd. for C H NO-HCI: C, 77.65; H, 8.25; N, 3.02. Found: C,77.90; H, 8.31; N, 3.11.

This compound exhibits the following activities: antiinflammatory;uterotrophic.

EXAMPLE 25 9- [p-( -dimeIhyZaminO rOpOxy) benzyl] fluorene When thehydrochloride of 9-[p-('y-dimethylaminopropoxy)benzal]fluorene replacedthe substituted fluorene in the procedure of Example 21, thehydrochloride salt of 9 [pOy-dimethylaminopropoxy)benzyllfluorene wasobtained (from isopropanol), melting at 2162l7 C.

Analysis.-Calcd. for C H NO-HCh C, 76.20; H, 7.16; N, 3.56. Found: C,75.55; H, 6.99; N, 3.59.

This compound exhibits the following activities: antiinfiammatory;estrogen antagonist; gonadotrophic inhibitor or androgen antagonist;decreases thyroid weight.

EXAMPLE 26 9-[p-(fi-pip ridinoethoxy)benzyllfluorene When thehydrochloride of 9-[p-(fi-piperidinoethoxy)- bcnzallfluorene replacedthe substituted fluorene in the procedure of Example 21, thehydrochloride salt of 9- [p (5 piperidinoethoxy)benzyllfiuorene wasobtained (from chloroform-isopropanol), melting at 228-230" C.

Analysis.-Calcd. for C H NO'HCl: C, 77.21; H, 7.20; N, 3.34. Found: C,76.64; H, 7.17; N, 3.56.

This compound exhibits the following activities: antiinflammatory; weakuterotrophic.

. EXAMPLE 27 9- [p-( fi-diethylaminoethoxy benzal] fluorene N -oxide Thefree base obtained by neutralizing 12 g. of the hydrochloride salt ofExample 3 was allowed to react in 200 ml. of methanol with 3.5 ml. of 30percent hydrogen peroxide for three days. The mixture was stirred with0.2 g. platinum oxide until oxygen evolution ceased, the catalyst wasremoved and the solution was concentrated under vacuum below 30 C. Etherwas added to the 12 gummy residue whereupon crystals of9-[p-(fi-diethylaminoethoxy)benzallfluorene N-oxide, existing as ahydrate, were obtained, decomposing at 111 C.

Anal.-Calcd. for c H No -H o; C, 77.40; H, 7.25; N, 3.46. Found: C,77.35; H, 7.42; N, 3.51.

EXAMPLE 28 9- i p- ,fi diethylaminoethoxy) benzal] fluorene methosulfateThe free base from 25 g. of the hydrochloride salt of Example 3 in 200ml. of dry ether was allowed to react with 8 g. of freshly distilleddimethylsulfate. After standing for three days, the ether was decantedand the residual yellow oil was triturated repeatedly with dry ether.The viscous gum was dissolved in about ml. of methylene chloride andthis solution wis diluted with 400 ml. of dry ether. The gummyprecipitate was allowed to stand under dry ether for two days whereuponsolidification of the entire mass finally was elfected. The solid wasdissolved in a minimum of ethanol and this solution was diluted withbutanone and a little dry ether. Crystals of the methosulfate of9-[p-(l8-diethylaminoethoxy)benzal]fluorene were obtained, melting at179- 180 C.

AnaL-Calcd. for C2eH27NO'(CH3)2SO4Z C, 67.86; H, 6.71. Found: C, 67.34;H, 6.70, N, 2.83, N, 2.89.

The compounds of the above examples exhibited the activities describedfor each (except anti-fungal activity and blood cholesterol andphospholipogenic activity) when administered parenterally(subcutaneously). Also, the compound of Example 20 exhibitedanti-inflammatory activity and the compounds of Examples 3, 7 and 11produced mouse lung consolidation arrest when administered orally. Thecompounds of Examples 4, 9, 15, 18, 20, 21 and 22 exhibited bloodcholesterol or phospholipogenic activity when administered orally. Thetests were carried out on mice and rats. Anti-fungal activity wasdetermined in vitro with the fungi described above.

The following examples illustrate suitable pharmaceutical preparationscontaining the new compounds. In these examples, the quantities aregiven for single units, it being understood that in actual practice, thedosage forms will be prepared in suitable quantities, and the amounts ofmaterials used adjusted accordingly.

EXAMPLE 29 25 MG. TABLETS Twenty-five mg. of the hydrochloride of9-[p-(fl-diethylaminoethoxy)benzallfluorene (Example 3). 48 mg. ofpowdered sugar, and 32 mg. of corn starch are mixed and granulated with10 percent gelatin solution. The granulation is dried and ground to finegranules for tableting. About 1 percent magnesium stearate is added as alubricant, together with suflicient corn starch to give a weight of 2.5grains per tablet. The product is compressed on a single punch or rotarymachine using a inch punch.

EXAMPLE 30 500 MG. TABLETS Five hundred mg. of the hydrochloride of9-[p-(fl-diethylaminoethoxy)benzallfluorene (Example 3) in finelypowdered form is admixed with 60 mg. of corn starch and 100 mg. ofpowdered sugar and then granulated with 10 percent gelatin solution. Thegranulation is dried and ground to size suitable for tableting. About 1percent magnesium stearate is added as a lubricant, together withsufficient corn starch to give a weight of 700 mg. per tablet. Theproduct is compressed on a single punch or rotary machine using a A inchpunch.

The tablets of Example 29 and Example 30 may be suitably coated ifdesired, as, for example, with sugar.-

3 .3 EXAMPLE 3.1 CAPSULE Twenty-five of the hydrochloride ofI-[p-(fl-dieth- 14 EXAMPLE 39 ISOTONIC SOLUTION, 0.25%

A mixture of 0.25 g. of the hydrqchloiide of MP-V/lIHIiIMfiOXJ/ibtllZt/ililtitflt (Example ii) is admired 5 (,6rliitlzylamiiioetlbry)benzallfiuorene (Example 3).

with corn starch in quantity required to provide suflicient bulk for thedesired size capsule, and the mixture is encapsulated.

EXAMPLE 32 CAPSULE Five hundred mg. of the hydrochloride of9-[p-(paminoethoxy)-benzyllfluorene (Example 20) is admixed withsufiicient corn starch to give the proper bulk for the desired sizecapsule, and the mixture is encapsulated.

EXAMPLE 33 INJECTABLE SUSPENSION, 100 MG. PER ML.

The following ingredients are sterilized separately: 100 mg. of thehydrochloride of 9-[p-(B-diethylaminoethoxy)benzal]fluorene (Example 3),0.1 mg. of Tween 80 and q.s. corn oil to make a final volume of 1 ml.These ingredients are admixed aseptically. Particle size may be achievedby use of micronized material or by use of a ball mill, maintainingaseptic conditions. The above suspension may be administeredsubcutaneously and intramuscularly.

EXAMPLE 34 LIQUID (SYRUP) 25 MG. PER TEASPOON Twenty-five mg. of thehydrochloride of 1-[p( 8-diethylaminoethoxy)benzal]indene (Example 15)is dissolved in 1 ml. of water. Five mg. of sodium benzoate, 3.5 ml. ofliquid sugar, 5 mg. of citric acid, and 0.375 mg. of butoben are addedand stirred until dissolved, using gentle heat if necessary. Flavor, asdesired, and water q.s. are then added.

EXAMPLE 35 LIQUID (SYRUP) 500 MG. PER TABLESPOON Five hundred mg. of thehydrochloride of 9-[p-(18-diethylaminoethoxy)benzallfiuorene (Example 3)and 4.5 mg. of sugar are dissolved in suflicient water so that after theaddition of 2.25 ml. of alcohol USP and flavor, as desired, the volumeis 15 ml.

EXAMPLE 36 INJECTABLE SOLUTION 100 MG. PER ML.

One hundred mg. of the hydrochloride of9-[p-(fl-diethylaminoethoxy)benzyl]fluorene (Example 3) and water forinjection q.s. 1 ml. are mixed and warmed gently till solution isaccomplished. The solution is filtered through fine sintered glass,filled into sterile 1 ml. ampuls, and sterilized at 250 F. for 30minutes.

EXAMPLE 37 1% OINTMENT To a melt of 1.5 lbs. of propylene glycol 6.68lbs. of polyethylene glycol 400 USP and 6.68 lbs. of carbowax 4000 USPis added 0.15 lb. of micropulverized hydrochloride of9-[p-(B-aminoethoxy)benzyllfluorene (Example 20). The product is stirreduntil almost solid and milled if necessary to a smooth ointment. Fill insuitable containers.

EXAMPLE 38 OINTMENT To a melt of 1.5 lbs. of propylene glycol, 6 lbs. ofpolyethylene glycol 400 USP and 6 lbs. carbowax 4000 USP is added 1.5lbs. of micropulverized hydrochloride of1-[p-(fl-aminoethoxy)benzyl]fluorene (Example 20). The product isstirred until almost solid and milled if necessary to a smooth ointment.Fill in suitable containers.

0.026 g. of methylparaben, 0.014 g. of propylparaben, 0.875 g. of sodiumchloride, and ml. of distilled Water is stirred until a clear solutionis obtained. Distilled water is added to make a final volume of ml. Thesolution is put in suitable containers for dispensing as nose drops, foratomizing, or for use in aerosol sprays.

EXAMPLE 40 ISOTONIC SOLUTION, 2%

A mixture of 2.0 g. of the hydrochloride of 9-[alpha-(B-diethylaminoethoxy)benzallfluorene (Example 3), 0.026 g. ofmethylparaben, 0.014 g. of propylparaben, 0.613 g. of sodium chloride,and 90 ml. of distilled Water is stirred until a clear solution isobtained. Distilled water is added to bring the final volume to 100 ml.The solution is put in suitable containers for dispensing as nose drops,for atomizing, or for use in aerosol sprays.

EXAMPLE 41 AEROSOL SPRAY, AQUEOUS Solutions from Examples 39 or 40 maybe placed into a pressurized container, pressurized with nitrogen,helium or a mixture of both, so that the initial head pressure is in therange of 65-75 pounds per square inch, and atomized through micro-mistvalves (available from Precision Valve Company).

Such a solution may also be metered through a number of differentaerosol valves to give a solution weight of from 25 mg. to 250 mg. percharge. (Such metered valves are available from Risdon Valve Company orAerosol Techniques, Inc.). Container size may be selected from any ofthe many available containers commercially available, varying in sizefrom 10 ml. to 8 ounces and made from glass, nylon, aluminum or coatedtin plate.

EXAMPLE 42 FREON PROPELLED AEROSOL Twenty grams of the hydrochloride of9-[p-(B-aminoethoxy)benzyllfluorene (Example 20) is dissolved in water,and 100 ml. 5 percent sodium hydroxide solution is added. The waterinsoluble oily base is extracted with ether; the ether extract is driedover anhydrous magnesium sulfate and evaporated on the steam bath andfinally in a vacuum desiccator. One gram of the residual oily free baseis dissolved in a mixture of 80 g. of Freon 114 and 20 g. of Freon 12in. the cold (20 C. or lower). The solution is cold filled into anappropriate pressure container. Such a container may have a gaugepressure of 18-25 pounds per square inch at normal room temperature andcan be dispensed from a metered valve.

We claim:

1. Compounds of the formula selected from the group consisting of O O HgA Y was from the group consisting of amino, alkylamino in which and 15316 the alkyl group contains from 1 to 4 carbon atoms, difiuorenyl,indenyl, tetrahydronaphthyl, xanthyl, thioalkylamino in which the alkylgroup contains from 1 to xanthyl and anthryl radicals.

4 carbon atoms, dibenzylarnino, morpholino, piperidino, 2.9-[p-(B-diethylaminoethoxy)benzalJfluorene. and N-methylpiperazinogroups; n is an integer of 2 to 3.9-[m-(fi-diethylaminoethoxy)benzal1fluorene. 3; Y is selected from thegroup consisting of hydrogen 5 4.9-[p-(fi-piperidinoethoxy)benzaflfluorene. and methyl; wherein R isselected from the group con- 5.1-[p-(,B-diethylaminoethoxy)benza11indene. sisting of fluorenylidene,indenylidene, tetrahydronaph- 6. 9-[p-(5-aminoethoxy)benzyflfiuorene.

thylidene, xanthylidene and thioxanthylidene radicals N r f r s ited.and wherein R is selected from the group consisting of o e 6 61166 c

1. COMPOUNDS OF THE FORMULA SELECTED FROM THE GROUP CONSISTING OF